1. Technical Field
The invention relates to an improved process for the production of powders of organic compounds by precipitation from liquid mixtures.
2. Background Information
The international patent application WO 98/2237 discloses a process for the production of inorganic powders by precipitation from a liquid reaction mixture, the method comprising passing along a tubular reactor a segmented reaction flow comprised of discrete volumes of the reaction mixture separated by discrete volumes of a separating fluid which is substantially immiscible with said reaction mixture, the residence time of said discrete volumes of reaction mixture in the reactor being sufficient for the precipitation reaction to be effected.
Unfortunately, this process is not applicable for inhalable medicaments.
For inhalable medicaments, a well-defined size and shape of the crystals is a pre-requisite. In order for a powdered compound or composition to be used in an inhaled medicament, the powder must have certain characteristics. For example, micronised medicaments or active ingredients generally come in solid form. In order to guarantee the inhalability of a powdered medicament, high requirements are placed on the particle size, the particle size distribution, the morphology, the stability and the flow performance of the powder holding the medicament.
In general, the entire administered dose of the medicament does not reach the lungs. Rather, only a part of the dose does. The particle size has a substantial influence on the proportion of the medicament which actually reaches the lungs. For this reason, particles are preferred which have a diameter of less than 20 μm, preferably less than 5 μm and greater than 0.3 μm. The diameter of the particle should be within the given window and furthermore should have the narrowest possible size distribution. Larger particles are separated off during respiration in the upper airways whilst smaller particles are not deposited in the lungs and these leave again when exhaling.
Therefore, there is a great requirement for processes which achieve powders of inhalable medicaments with uniform shape, small size and narrow size distribution.
It is known that crystallization of drug actives can be ultrasonically promoted, e.g. Causland and Cains in Drug Delivery Systems & Sciences, Volume 2 No. 2, June/July 2002, pp. 47-51.
However, there is no hint that the application of ultrasound to a tubular reactor with a segmented reaction flow would yield such a desired crystal formation.